Applications of Liver Humanized Mouse Models in Preclinical Drug Development

Animal models are traditionally used in the drug development process to determine the safety and efficacy of new drug candidates. Yet, translation between animals and humans is not always straightforward due to inherent differences between species. A promising way to bridge this gap has been the development of chimeric mice possessing humanized livers. Over the past two decades, much progress has been made in the development of mouse models which are able to achieve at least 70% replacement of mouse hepatocytes with human hepatocytes. This has enabled the use of these models for an increasing variety of applications in the preclinical drug development process.

The first segment of this webinar will focus on the genetic basis of these liver-humanized mouse models, as well as their historical development and characterization. The second and major segment of the presentation will illustrate their use in a wide variety of in vivo and in vitro applications over the past decade. These include liver disease models such as hepatitis B and C virus infection. Numerous publications have described the use of liver-humanized mouse models for studies on drug metabolism and pharmacokinetics, enzyme induction, drug clearance projections, identification of human metabolites and the prediction of clinically relevant drug-drug interactions. Liver toxicity studies have been carried out both in vivo and in vitro, the latter utilizing hepatocytes isolated from these liver humanized mice. Finally, these models are useful to test the delivery of gene therapy reagents to the liver, as well as to repopulate the liver with genetically modified hepatocytes. The advent of the chimeric mouse model presents the drug discovery investigator with an effective range of approaches to predict clinically relevant pharmacology, metabolism and safety of traditional and novel therapeutics.

Speaker

David Thompson, Ph.D., Sr. Director, Mechanistic Pharmacology & Toxicology, Inotiv

David Thompson is the Sr. Director of Mechanistic Pharmacology and Toxicology at Inotiv. He joined Inotiv in 2019 to create and lead a team focused on utilizing state of the art in vitro molecular and cell-based tools to address pharmacological and toxicological issues. His group is part of an Integrated Discovery Center that includes expertise in preclinical animal studies, DMPK and pathology. Thompson received his Ph.D. in biochemical toxicology from Johns Hopkins University followed by post-doctoral fellowships at Karolinska Institute and NIEHS. He spent most of his career in the pharmaceutical industry as a member of drug safety teams and manager of an investigative toxicology laboratory. Prior to joining Inotiv, he managed an R&D group focused on the development of ADME/Tox cell-based bioassays including genetically modified cell lines targeting transporter and drug metabolism pathways. 

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